treatment of an inherited ventricular arrhythmia

Conditions: Catecholaminergic Polymorphic Ventricular Tachycardia Type 1

Summary: the goal of the proposed project is to determine the safety and tolerability as well as the preliminary efficacy of a novel small molecule drug, s48168 (arm210), for the treatment of catecholaminergic polymorphic ventricular tachycardia (cpvt1). this disease is associated with fatal changes in heart rhythms leading to sudden death with exercise or excessive excitement. it is due to mutations in the ryanodine receptor calcium release channel, which cause leaky channels leading to the disease. s48168 (arm210) repairs these leaky channels and can be a disease-modifying therapy restoring normal function to the channels. this result would allow patients with cpvt to live normal, active lives. funding source- fda oopd.


Eligibility criteria:
inclusion criteria: participants must meet all the following conditions to be eligible for enrollment into the study: 1. participant must be 18 to 65 years of age inclusive, at the time of signing the informed consent. 2. participants who are willing and able to comply with scheduled visits, study drug administration plan, study restrictions, and study procedures. 3. participants have a confirmed genetic diagnosis of cpvt1 and supporting clinical phenotype, including residual ventricular ectopy (a complexity score ≥ 2; requiring at minimum the presence of pvcs in bigeminy on exercise stress test) on a stable (at least 1 month) standard-of-care, cpvt1-directed treatment regimen as decided by their cpvt treating physician. 4. have a body mass index (bmi) ≤ 36 kg/m2 (inclusive) at screening. 5. male participants agree to not donate sperm from the first day of dosing of study drug until 5 half-lives plus 90 days (approximately 94 days) after the last dose of study drug. female participants: eligible to participate if she is not pregnant or breastfeeding, and uses one of the following highly effective birth control methods (from the first dose until 5 half-lives plus 90 days (approximately 94 days): * prescribed hormonal oral contraceptives, vaginal ring, or transdermal patch. * intrauterine device (iud). * intrauterine hormone-releasing system (ius). * depot/implantable hormone (e.g., depo-provera®, implanon). * bilateral tubal occlusion/ligation. * sexual abstinence. * refraining from heterosexual intercourse during the entire period of risk associated with the study requirements. * if the participant decides to become sexually active during the study, then one of the highly effective birth control methods must be used. or is a woman of non-childbearing potential; defined by at least 1 of the following criteria: * postmenopausal defined as 12 months of spontaneous amenorrhea without a medical cause and follicle stimulating hormone (fsh) serum level \> 40 miu/ml without the use of hormonal supplementation. appropriated documentation of fsh levels is required. * surgically sterile by hysterectomy and/or bilateral oophorectomy with appropriate documentation of surgical procedure. * has a congenital condition resulting in no uterus. 6. capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (icf) and in the protocol. 7. daily use of medicines and dietary supplements need to be approved by the pi and sponsor, or a drug/supplement-dependent wash-out prior to inclusion. exclusion criteria: the presence of any of the following conditions will exclude a participant from study enrollment: 1. history or presence of alcoholism or drug abuse within the past 2 years prior to the first dose of study drug. 2. history or presence of hypersensitivity or idiosyncratic reaction to the study drug, related compounds, or inactive ingredients. 3. alt or ast levels three times above the upper limits of normal (uln) at screening (isolated elevations of total bilirubin \< 2 x uln with direct bilirubin below the uln will be included). a recheck for confirmation is allowed. 4. history of documented, eeg-confirmed epileptic seizures. 5. history of cancer (malignancy). exceptions: (1) subjects with adequately treated non-melanomatous carcinoma or carcinoma in situ of the cervix may participate in the trial; (2) subjects with other malignancies who have been successfully treated \> 10 years prior to the screening where in the judgment of the investigator has revealed no evidence of recurrence from the time of treatment through the time of the screening except those identified at the beginning of the exclusion criterion; or (3) subjects who in the opinion of the investigator are highly unlikely to sustain a recurrence for the duration of the trial. 6. currently has uncontrolled diabetes defined as hba1c \> 7% at screening visit or diabetic neuropathy. 7. estimated creatinine clearance \< 40ml/minute at screening visit. 8. clinically significant abnormality on their screening and/or prior to first dosing resting ecg, other than hypertensive related, or heart failure (ejection fraction \< 30%) or other clinically significant structural heart disease. 9. history of myocardial infarction in the last five years, or evidence of congestive heart failure. 10. ongoing medical condition that is deemed by the pi to interfere with the conduct or assessments of the study or safety of the subject. 11. unable to refrain from or anticipates the use of: * any non-approved medicines (prescribed standard-of-care for cpvt is approved) and/or dietary supplements beginning 14 days prior to the first dose of study drug and throughout the study. thyroid hormone replacement medication may be permitted if subject has been on same stable dose for the last 3 months prior to the first dose of study drug. * any drugs known to be significant inducers or inhibitors of cyp2c8 enzymes for 28 days prior to the first dose of study drug and throughout the study. is currently taking any drug which raises gastric ph, including proton pump inhibitors or h2 antagonists. antacids may be used if taken at night. 12. participation in clinical trials for other therapeutic investigational drugs simultaneously or within the 4 weeks prior to the first dose of study drug. 13. plasma donation within 7 days prior to the first dose of study drug. 14. donation of blood or significant blood loss within 56 days prior to the first dose of study drug. 15. is mentally or legally incapacitated at the time of screening visit. 16. is unable to take orally administered tablets. 17. is an immediate family member of the sponsor or employee of the clinical site or may consent under duress.

Keywords: ventricular arrhythmia calcium ryanodine receptor 2